PROJECT SUMMARY/ABSTRACT The newly-formed Risk, Detection and Outcomes (RDO) Program has 49 members (47 primary, 2 associate) from 19 departments and is led by Drs. Paul Scheet (human genetics, computational biology) with co-leaders Sanjay Shete (biostatistics, genetic epidemiology, population health), Samir Hanash (early detection, proteomics), and Sharon Giordano (health care delivery, outcomes). The major scientific goal of the RDO Program is to reduce the cancer burden in the population and improve quality of life in survivors through innovative research aimed at optimizing cancer risk assessment, screening, early detection, and treatment- associated outcomes from diagnosis through survivorship, with an ultimate goal of informing successful interventions (e.g., in the Cancer Prevention Program). To achieve this goal, the RDO Program is organized into 3 specific aims focusing on 1) Cancer Etiology, 2) Early Detection, and 3) Care Delivery and Outcomes. Aim 1: To discover genetic, behavioral, and environmental factors for cancer initiation. Aim 2: To perform biomarker discovery for personalized risk assessment and early detection. Aim 3: To identify biological and social factors influencing care delivery and patient outcomes. The annual direct peer-reviewed funding of the RDO Program totals $11.4M, including 4 U01s, of which $5.4M (47%) is from the NCI. Over the past 6 years, program members have authored 1211 published peer-reviewed papers, with 373 (31%) intra-programmatic, 594 (49%) inter- programmatic, and 877 (72%) external collaborations. Forty-five percent of articles appeared in journals with IF >5, and 14% appeared in journals with IF >10, including Nat Biotechnol, Nat Genet and J Clin Oncol. Program members used all 14 shared resources. Over this period, the RDO Program has had several major accomplishments. First, in whole-genome genetic epidemiology studies, we identified genetic variants that predispose to disease initiation, affect outcomes, or predict adverse responses to therapy. In multiple whole- exome next-generation sequencing studies, the first of their kind, we are powered to discover variants of higher, intermediate cancer risk. We have also surveyed genomic changes in precancerous tissues, shedding light on early disease pathology. Second, we have uncovered novel blood-based biomarkers for early detection through state-of-the-art profiling technologies. Key hits identified from proteomics and metabolomics promise to complement low-dose CT scans in individuals at high risk for lung cancer. Third, as leaders in a consortium of Texas academic institutions and the Texas Cancer Registry, we have studied patterns of screening, diagnosis, treatment (e.g., chemotherapy and associated decision-making), and follow-up to impact state-wide policy. For all of these endeavors, we continue to develop and enhance unique cohorts, including Cancer Patients and Survivors, Mexican American, Premalignant Genome Atlas, Childhood Cancer Survivors, and organ-specific cohorts of the lung, breast, and ovary.